Current treatment of motor neuron disorders, such as ALS, spinal cord injury, spinal cord stroke, or spinal cord ischemia, is mainly ineffective due to the non-selective, systemic and often indirect nature of cell or drug delivery. Numerous pre-clinical studies on development of stem cell-based therapies for neurodegenerative disorders or other pathological conditions primarily focus on system (intravenous) routes of cell transplantation (Sanberg, et al., Navigating cellular repair for the central nervous system. Clin Neurosurg. 2008; 55:133-137; Willing, et al., Routes of stem cell administration in the adult rodent. Methods Mol Biol. 2008; 438:383-401; Hess & Borlongan, Stem cells and neurological diseases. Cell Prolif. 2008 February; 41 Suppl 1:94-114; Ehrhart, et al., Distribution of infused human umbilical cord blood cells in Alzheimer's disease-like murine model. Cell Transplant. 2015 Sep. 25; PMID 26414627). Though there have been some promising results, there are significant limitations due to cell migration to CNS tissue, specifically in the spinal cord, possible due to the non-selective and often indirect nature of cell delivery. In a mouse model of amyotrophic lateral sclerosis (ALS), a single repeated IV injection of human umbilical cord blood cells (hUCBCs) resulted in wide distribution of cells within and outside the CNS (Garbuzova-Davis, et al., Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res. 2003 June; 12(3):255-270; Garbuzova-Davis, et al., Multiple intravenous administrations of human umbilical cord blood cells benefit in a mouse model of ALS. PLoS ONE. 2012; 7(2):e31254). While some cells were found in the brain and spinal cord, most cells were distributed in the peripheral organs, mainly the spleen. Other studies optimizing hUCBC doses for ALS treatment showed toxicity at the highest IV dose (50×106), similar to graft-versus-host disease (Garbuzova-Davis, et al., Human umbilical cord blood treatment in a mouse model of ALS: optimization of cell dose. PLoS ONE. 2008; 3(6):e2494). A study of hUCBC treatment of the metabolic disorder MPS IIIB showed limited cell migration into the brain of knockout mice modeling the disease after either lateral cerebral ventricle (Garbuzova-Davis, et al., Transplantation of human umbilical cord blood cells benefits an animal model of Sanfilippo syndrome type B. Stem Cells Dev. 2005 August; 14(4):384-9394) or IV cell infusion (Garbuzova-Davis, et al., Intravenous administration of human umbilical cord blood cells in an animal model of MPS IIIB. J Comp Neurol. 2009 Jul. 1; 515(1):93-101; Willing, et al., Repeated administrations of human umbilical cord blood cells improve disease outcomes in a mouse model of Sanfilippo syndrome type III B. Cell Transplant. 2014; 23(12):1613-1630).
In middle cerebral artery occlusion (MCAO) rat models of ischemic stroke, though IV administration of hUCBC at different doses showed benefits in behavior recovery, and reduced brain infarct volumes, the transplanted cells mainly congregated in the spleen (Vendrame, et al., Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 2004 October; 35(10):2390-2395; Vendrame, et al., Cord blood rescues stroke-induced changes in splenocyte phenotype and function. Exp Neurol. 2006 May; 199(1):191-200). Other studies have shown no effect on neurological deficit or infarct volume after IV transplant of hUCBC, attributed to a lack of cell migration to the ischemic tissue (Zawadzka, et al., Lack of migration and neurological benefits after infusion of umbilical cord blood cells in ischemic brain injury. Acta Neurobiol Exp (Wars). 2009; 69(1):46-51; Makinen, et al., Human umbilical cord blood cells do not improve sensorimotor or cognitive outcome following transient middle cerebral artery occlusion in rats. Brain Res. 2006 Dec. 6; 1123(1):207-215). A recent study has found human bone marrow stromal cells, when IV administered into chronic post-stroke rats, migrated to the spleen, but not the brain (Acosta, et al., Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke. 2015 September; 46(9):2616-2627), while another study showed IV administration of bone marrow-derived mesenchymal stem cells (BM-MSCs). In early post-stroke rats was associated with better functional recovery and cell migration to the cortex (Lee, et al., Differential migration of mesenchymal stem cells to ischemic regions after middle cerebral artery occlusion in rats. PLoS ONE. 2015; 10(8):e0134920). Other studies have demonstrated that intra-arterial (IA) administration of human BM-MSCs is more efficient than IV administration in treating cerebral ischemia in rats (Du, et al., Intra-arterial delivery of human bone marrow mesenchymal stem cells is a safe and effective way to treat cerebral ischemia in rats. Cell transplant. 2014; 23 Suppl 1:S73-82; Mitkari, et al., Intra-arterial infusion of human bone marrow-derived mesenchymal stem cells results in transient localization in the brain after cerebral ischemia in rats. Exp Neurol. 2013 January; 239:158-162), due to direct cell migration to ischemic areas of the brain. Moreover, IA cell administration into MCAO rats at 24 hours post-stroke provides better functional recovery and reduction of infarct volumes (Toyoshima, et al., Intra-arterial transplantation of allogeneic mesenchymal stem cells mounts neuroprotective effects in a transient ischemic stroke model in rats: analyses of therapeutic time window and its mechanisms. PLoS ONE. 2015; 10(6):e0127302).
In a study analyzing in vivo distribution of rat BM-MSCs administered into syngenic rats via IV or IA routes, MSCs were detected primarily in the lungs, followed by the liver, then other organs, after both types of administration (Gao, et al., The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusions. Cells tissues Organs. 2001; 169(1):12-20). Another study investigating feasibility of allogenic GFP-labeled BM-MSCs via IV transplantation in a rabbit model of femoral head necrosis showed cell migration to the lungs, liver, bone marrow, normal and necrotic femoral heads (Li, et al., Intravenous transplantation of allogeneic bone marrow mesenchymal stem cells and its directional migration to the necrotic femoral head. Int J Med Sci. 2011; 8(1):74-83). Administration of human adipose-derived mesenchymal cells into sublethally irradiated immune-deficient mice via IV, intraperitoneal, or subcutaneous routes showed cell distribution in multiple tissues across the various routes (Meyerrose, et al., In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells. 2007 January; 25(1):220-227). These results indicate multiple homing cites for transplanted cells and the likelihood that cell distribution is deleteriously influenced by indirect administration.
In a rabbit spinal cord injury model, rabbit BM-MSCs induced into neuronal-like cells were transplanted into the subarachnoid space and shown to migrate to the spinal cord injury region and improve functional recovery (Zhang, et al., In vivo tracking of neuronal-like cells by magnetic resonance in rabbit models of spinal cord injury. Neural Regen Res. 2013 Dec. 25; 8(36):3373-3381). A similar neuroprotective effect was observed after injection of placenta-derived mesenchymal stem ells into injured rabbit spinal cord (tan, et al., Neuroprotective effect of methylprednisolone combined with placenta-derived mesenchymal stem cell in rabbit model of spinal cord injury. Int J Clin Exp Pathol. 2015; 8(8):8976-8982). Although some benefits of local cell transplant have been observed, possible Wallerian degeneration of axons distal form the lesion may obstruct full motor recovery. Despite intensive investigations of various treatment options for spinal cord injury/motor neuron disorders, current stem cell-based therapeutics for the pathological spinal cord have limited efficacy. Additionally, systemic intravenous or parenchymal administration of therapeutics provides limited distribution or cell migration within the spinal cord in various animal models of disease, leading to inadequate efficacy, inefficient utilization of costly resources, and significant risk for systemic toxicity. As a result, despite intense investigation, current stem cell-based therapeutics for spinal cord disorders have shown limited benefit.
As such, the inventive method provides direct stem cell transplantation into the spinal cord thereby significantly improving efficiency of delivery and successful uptake of the cells in target tissues that will lead to better therapeutic outcomes compared to systemic delivery. The present device and methods are envisioned useful for pharmacotherapies, as well as existing cell-based therapies, and gene therapies. Furthermore, localized cell delivery into the spinal cord, as opposed to systemic infusion, will require a much smaller dose of therapeutics and be more cost effective. Thus, direct administration of stem cells and other therapeutic agents to the spinal cord addresses the shortcomings of prior administration methods by providing concentrated, site-directed delivery to target tissues. This method will improve treatment options for motor neuron degenerative diseases, such as perioperative spinal cord ischemia, ALS, spinal cord injury, spinal cord stroke, or other spinal cord ischemia.
This invention consists of a novel non-invasive method for direct delivery of therapeutics (stem cells or drugs) to the spinal cord in the treatment of spinal cord pathology. Using fluoroscopic imaging, a guide wire would be inserted via percutaneous stick into the femoral artery and then threaded up into the vertebral arteries; once in place, a dual balloon catheter would be guided to a point above the segmental cervical spinal arteries (i.e. ascending cervical, anterior spinal artery, anterior radicular artery) and used to segmentally occlude the vessel and prevent blood access to the brain during injection of therapeutics. The catheter has infusion ports between the two occlusion balloons which would allow for injection of therapeutics directly into the segmental spinal arteries without risking brain or systemic exposure. Once the therapeutic agents have been delivered selectively to the spinal cord, the balloon would be deflated and removed. This same approach could also be used to occlude and isolate segments of the thoracic or abdominal aorta to deliver therapeutics through segmental thoracic or lumbar spinal arteries to more selectively target disease processes in these regions.
Using this novel technique, therapeutics of interest could be selectively delivered to a discrete region of the spinal cord to increase efficacy of treatment and minimize intracranial or systemic exposure. This invention has multiple applications in treatment of neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), traumatic spinal cord injury, spinal cord stroke, and perioperative spinal cord ischemia during vascular procedures.
Systemic intravenous administration of therapeutics provides limited cell or drug distribution within the spinal cord in various animal models of disease, leading to limited efficacy and the utilization of inefficiently and costly high dosages with significant risk for systemic toxicity. The novel method described here will allow a selective, safe and effective, non-invasive approach to treating specific spinal cord disorders. An additional benefit of this method will be the avoidance of superfluous cell or drug distribution to non-spinal cord areas with resulting toxicity. Moreover, localized delivery into the spinal cord, as opposed to systemic infusion (as in the case of intravenous approach), will require a much smaller dose of therapeutics to afford efficacy. This invention might prompt improved therapies for a wide range of neurodegenerative and ischemic disorders.